The present invention relates to novel antidiabetic compounds, their tautomeric forms. their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts. their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. This invention particularly relates to novel azolidinedione derivatives of the general formula (I), and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. 
The present invention also relates to a process for the preparation of the above said novel, azolidinedione derivatives, their tautomeric for their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them.
The azolidinedione derivatives of the general formula (I) defined above of the present invention are usefull for the treatment and/or prophylaxis of diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases and conditions are type II diabetes, impaired glucose tolerance, dyslipidermia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis. The azoldinedione derivatives of the formula (I) are usefull for the treatment of insulin resistance associated with obesity and psoriasis. The azolidinedione derivatives of the formula (I) can also be used to treat diabetic complications and can be used for treatment and/or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia.
Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect: failing which, the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985)75: 809-817; N. Engl. J. Med.; (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X. In addition, polycystic ovarian syndrome (Patent Application No. WO 95/07697), psoriasis (Patent Application No. WO 95/35108). dementia (Behavioral Brain Research (1996) 75: 1-11) etc. may also have insulin resistance as a central pathogenic feature.
A number of molecular defects have been associated with insulin resistance. These include reduced expression of insulin receptors on the plasma membrane of insulin responsive cells and alterations in the signal transduction pathways that become activated after insulin binds to its receptor including glucose transport and glycogen synthesis.
Since defective insulin action is thought to be more important than failure of insulin secretion in the development of non-insulin dependent diabetes mellitus and other related complications, this raises doubts about the intrinsic suitability of antidiabetic treatment that is based entirely upon stimulation of insulin release. Recently, Takeda has developed a new class of compounds which are the derivatives of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref. Chem. Pharm. Bull. 1982, 30, 3580-3600). In the formula (II), V represents substituted or unsubstituted divalent aromatic group and U represents various groups which have been reported in various patent documents. 
By way of examples, U may represent the following groups: (i) a group of the formula (IIa) where R1 is hydrogen or hydrocarbon residue or heterocyclic residue which may each be substituted, R2 is hydrogen or a lower alkyl which may be substituted by hydroxy group, X is an oxygen or sulphur atom, Z is a hydroxylated methylene or a carbonyl, m is 0 or 1, n is an integer of 1-3. These compounds have been disclosed in the European Patent Application No. 0 177 353 
An example of these compounds is shown in formula (IIb) 
(ii) a group of the formula (IIc) wherein R1 and R2 are the same or different and each represents hydrogen or C1-C5 alkyl, R3 represents hydrogen, acyl group, a (C1-C6) alkoxycarbonyl group or aralkyloxycarbonyl group, R4-R5 are same or different and each represent hydrogen, C1-C5 alkyl or C1-C5 alkoxy or R4, R5 together represent C1-C4 alkenedioxy group, n is 1, 2, or 3, W represents CH2, CO, CHOR6 group in which R6 represents any one of the items or groups defined for R3 and may be the same or different from R3. These compounds are disclosed in the European Patent Application No. 0 139 421. 
An example of these compounds is shown in (IId) 
iii) A group of formula (IIe) where A1 represents substituted or unsubstituted aromatic heterocyclic group. R1 represents a hydrogen atom, alkyl group, acyl group, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group, n represents an integer in the range from 2 to 6. These compounds are disclosed in European Patent No. 0 306 228. 
An example of this compound is shown in formula (IIf) 
iv) A group of formula (IIg) where Y represents N or CR5, R1, R2, R3, R4 and R5 represents hydrogen, halogen, alkyl and the like and R6 represents hydrogen, alkyl, aryl and the like, n represents an integer of 0 to 3. These compounds are disclosed in European Patent Application No. 0 604 983. 
An example of this compound is shown in formula (IIh) 
Still another class of antihyperglycemic agents are 5-substituted oxazolidine-2,4-diones and 2-substituted-1,2,4-oxadiazolidine-3,5-diones which can be represented in the formula (IIi), 
where V represents substituted or unsubstituted divalent aryl or hetero aryl group, W represents various groups which have been reported in various patent documents, A represents nitrogen atom or a CH group and B is an oxygen atom.
By way of examples, W may represent the following groups: v) a group of formula (IIj), where R is (C1-C6) alkyl groups, cycloalkyl group, furyl, thienyl, substituted or unsubstituted phenyl group, X is hydrogen, methyl, methoxy, chloro or fluoro. These compounds have been disclosed in the U.S. Pat. No. 5,037,842. 
An example of these compounds is shown in formula (IIk). 
(vi) A group of formula (III) wherein A1 represents a substituted or unsubstituted aromatic heterocyclyl group; R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted or a substituted or unsubstituted aryl group, n represents an integer in the range of from 2 to 6. These compounds have been disclosed in the patent application No. WO 92/02520. 
An example of these compounds is shown in formula (IIm). 
(vii) A group of formulae (IIn) and (IIo), where R1 is hydrogen, (C1-C8)alkyl, (C1-C8)alkoxy, trifluoroalkoxy, halogen or trifluoromethyl group, R2 is hydrogen or methyl and X is oxygen or sulfur. These compounds have been described in U.S. Pat. No. 5,480,486. 
An example of these compounds is shown in formula (IIp) 
Some of the above referenced hitherto known antidiabetic compounds seem to possess bone marrow depression, liver and cardiac toxicities and modest potency and consequently, their regular use for the treatment and control of diabetes is becoming limited and restricted.
With an objective of developing new compounds for the treatment of type II diabetes [non-insulin-dependent-diabetes mellitus (NIDDM)] which could be more potent at relatively lower doses and having better efficacy with lower toxicity, we focused our research efforts in a direction of incorporating safety and to have better efficacy, which has resulted in the development of novel azolidinedione derivatives having the general formula (I) as defined above.
The main objective of the present invention is therefore, to provide novel azolidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
Another objective of the present invention is to provide novel azolidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, no toxic effect or reduced toxic effect.
Yet another objective of the present invention is to produce a process for the preparation of novel azolidinediones of the formula (I) as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their tautomers, their stereoisomers, their polymorphs, their salts, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Yet another objective of the present invention is to provide a process for the preparation of the novel intermediate of the formula (III) 
where G represents xe2x80x94CHO, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CHxe2x95x90NHOH, xe2x80x94CH2NHOH, xe2x80x94CH2N(OH)CONH2 or xe2x80x94CH2CH(J)xe2x80x94COOR, where J represents hydroxy group, halogen atom such as chlorine, bromine or iodine and R represents H or lower alkyl group such as methyl, ethyl, or propyl, X, Y, Z, R1, R2, R3, n, and Ar are defined as in formula (I).
Azolidinedione derivatives of the present invention have the general formula (I) 
In the above formula (I), one of X, Y or Z represents Cxe2x95x90O or Cxe2x95x90S and the remaining of X, Y and Z represent a group Cxe2x95x90 or Cxe2x95x90C; R1, R2 and R3 are groups either on X, Y or Z or on a nitrogen atom R1, R2 and R3 may be same or different and represent hydrogen, halogen, hydroxy, or nitro, or optionally substituted groups selected from alkyl; cycloalkyl alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives with the provision that when R1, R2 or R3 is on a nitrogen atom it does not represent hydrogen, halogen, nitro, carboxylic acid or sulfonic acid groups; or any two of R1, R2 and R3 along with the adjacent atoms to which they are attached may also form a substituted or unsubstituted cyclic structure of from 4 to 7 atoms with one or more double bonds, the cyclic structure may be carbocyclic or may contain one or more heteroatoms selected from oxygen, nitrogen and sulfur. When the groups representing R1, R2 or R3 are substituted, the substituents are selected from the same groups that may represent R1, R2, and R3 such as hydroxy, halogen, or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. The linking group represented by xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 in formula (I) may be attached either through nitrogen atom or through X, Y or Z where n is an integer ranging from 1-4. Ar represents an optionally substituted divalent aromatic or heterocyclic group, R4 represents hydrogen atom, halogen or lower alkyl group or forms a bond together with the adjacent group A. A represents a nitrogen atom or a group CR5 where R5 represents hydrogen, halogen or lower alkyl group such as methyl, ethyl, propyl or the like or R5 forms a bond together with R4; B represents an oxygen atom or a sulfur atom when A is CR5 and B represents an oxygen atom when A is a nitrogen atom.
Suitable combinations of X, Y and Z that form the ring structure containing X, Y and Z in the formula (I) are represented in the following Table:
It is preferred that at least one of X, Y or Z be Cxe2x95x90C.
It is preferred that one of X or Y be Cxe2x95x90O. Suitable ring structures containing X, Y and Z include 
A preferred ring structure is 
When R1, R2 and R3 groups are attached to X, Y, and Z it is preferred that R1, R2, and R3 are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, nitro; substituted or unsubstituted (C1-C12)alkyl group, especially, linear or branched (C1-C6)alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl and the like; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like; aryl group such as phenyl or naphthyl, the aryl group may be substituted; aralkyl such as benzyl or phenethyl, the aralkyl group may be substituted; heteroaryl group such as pyridyl, thienyl, fluryl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl and the like, the heterocyclyl group may be substituted; aryloxy such as phenoxy, naphthyloxy, the aryloxy group may be substituted; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl; aryloxycarbonyl group such as optionally substituted phenoxycarbonyl; arylamino group such as HNC6H5; amino group; amino(C1-C6)alkyl; hydroxy(C1-C6)alkyl; (C1-C6)alkoxy; thio(C1-C6)alkyl; (C1-C6)alkylthio; acyl group such as acetyl, propionyl or benzoyl, the acyl group may be substituted; acylamino groups such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC6H5, aralkoxycarbonylamino group such as NHCOOCH2C6H5, alkoxycarbonylamino group such as NHCOOC2H5, NHCOOCH3 and the like; carboxylic acid or its derivatives such as amides, like CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like, the carboxylic acid derivatives may be substituted; acyloxy group such as OCOMe, OCOEt, OCOPh and the like which may optionally be substituted; sulfonic acid or its derivatives such as SO2NH2, SO2NHMe, SO2NMe2, SO2NHCF3 and the like; the sulfonic acid derivatives may be substituted.
All of the preferred groups that may represent R1, R2 and R3 may be substituted or unsubstituted.
When R1, R2 or R3 are attached to nitrogen atom, it is preferred that R1, R2 and R3 are selected from (C1-C12)alkyl group, especially linear or branched (C1-C6)alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl groups and the like; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; aryl group such as phenyl or naphthyl; aralkyl such as benzyl or phenethyl; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl and the like; heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl and the like; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl; aryloxycarbonyl group such as phenoxycarbonyl; amino(C1-C6)alkyl; hydroxy(C1-C6)alkyl; thio(C1-C6)alkyl; or acyl group such as acetyl propionyl, benzoyl, and the like.
All of the preferred groups that may represent R1, R2 and R3 may be substituted or unsubstituted.
When the groups represented by R1, R2 and R3 are substituted, the substituents selected are from the same groups as those groups that represent R1, R2 and R3 and may be selected from halogen, hydroxy, or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
Suitable ring structure formed by any two of R1, R2 and R3 along with the adjacent atoms to which they are attached, include substituted or unsubstituted 4-7 membered cyclic structure which may contain one or more double bonds, the cyclic structure may be carbocyclic or optionally contains one or more hetero atoms selected from nitrogen, oxygen and sulfuir. Examples of the cyclic structures are phenyl, naphthyl, thienyl, furyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, azacyclobutenyl, isoxazolyl, azepinyl, pyridyl, pyridazyl, pyrimidinyl, dihydrofuryl, dihydrothienyl, tetrahydropyridyl, tetrahydrophenyl, tetrahydronaphthyl and the like. The substituents on the cyclic structure maybe selected from the same groups as that of R1, R2 and R3. Examples of possible substituents are halogen, alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, hydroxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
It is more preferred that R1, R2 and R3 groups represent hydrogen; halogen atom such as fluorine, chlorine, bromine, or iodine; alkyl group such as methyl, ethyl, n-propyl or n-butyl; cycloalkyl group such as cyclopropyl; aryl group such as phenyl; or aralkyl group such as benzyl.
When the groups represented by R1, R2 and R3 are substituted, it is preferred that the substituents are selected from halogen, haloalkyl, haloalkoxy, and halocycloalkoxy wherein the halogen atom is preferably a fluorine atom.
The ring structure formed by any two of R1, R2 and R3 along with the adjacent atoms to which they are attached, may be substituted or unsubstituted. Preferred ring structures are phenyl, thienyl, furyl or pyridyl groups. When these ring structures are substituted, it is preferred that the substituents are selected from halogen, lower alkyl group such as methyl or ethyl; trifluoromethyl; fluoromethyl; difluoromethyl; and alkoxy groups such as methoxy, trifluoromethoxy, fluoromethoxy and difluoromethoxy.
The linking group xe2x80x94(CH2)nxe2x80x94 may be linked either through a nitrogen atom or through X, Y or Z. The integer n may range from 1 to 4, preferably n is 1 to 2. It is preferred that the linking group be linked either through nitrogen or through Z when Z represents xe2x95x90C.
It is preferred that the group represented by Ar be substituted or unsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. The substituents on the group represented by Ar may be selected from linear or branched (C1-C6)alkyl, (C1-C3)alkoxy, halogen, acyl, amino, acylainino, thio, or carboxylic or sulfonic acids or their derivatives.
It is more preferred that Ar represents substituted or unsubstituted divalent plleylene, naphthylene, benzofuryl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl.
It is still more preferred that Ar is represented by divalent phenylene or naphthylene, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups.
Suitable R4 includes hydrogen; lower alkyl group such as methyl, ethyl or propyl; halogen atom such as fluorine, chlorine, bromine or iodine, or R4 together with A represents a bond.
Suitable A group may be nitrogen or CR5 where R5 may be a hydrogen atom, halogen, lower alkyl group or together with R4 forms a bond.
Suitable B group includes a hetero atom selected from O or S, with the provision that when A is CR5, B is selected from sulfur or oxygen, and when A is nitrogen, B represents oxygen.
Suitable ring structure comprising A and B include 2,4-dioxooxazolidin-5-yl, 2,4-dioxothiazolidin-5-yl, 3,5-dioxo1,2,4-oxadiazolidin-2-yl groups. Preferred ring structures comprising, A and B, include 2,4-dioxooxazolidine-5-yl and 2,4-dioxothiazolidin-5-yl groups.
It is more preferred that the ring structure comprising A and B is a 2,4-dioxothiazolidin-5-yl group.
Pharmaceutically acceptable salts forming part of this invention include salts of the azolidinedione moiety such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidinie, diethanolamine, choline and the like, ammonium or substituted ammonium salts, salts of carboxy group wherever appropriate, such as aluminumn, alkali metal salts; alkaline earth metal salts, ammonium or substituted ammonium salts. Salts may include acid addition salts which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Particularly usefull compounds according to the present invention includes:
5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione and its salts and its polymorphs.
5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quiazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[6,7-dimethoxy-2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]oxazolidine-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]oxazolidine-2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]oxazolidine-2,4-dione and its salts,
2-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,
2-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,
2-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,
5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-3-methoxyphenyl methylene]thiazolidine-2,4-dione and its salts,
More preferred compounds according to the present invention include
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione, 5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt,
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione and its polymorphs,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt and its polymorphs,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione, potassium salt,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione, sodium salt.
According to a feature of the present invention, there is provided a process for the preparation of novel intermediate of the general formula (III) 
where X, Y, Z, R1, R2, R3 and n are as defined earlier, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 linker is attached to nitrogen atom, G represents xe2x80x94CHO or xe2x80x94NO2 group which comprises, reacting a compound of the general formula (IV) 
where X, Y, Z, R1, R2 and R3 are as defined earlier and H atom is attached to one of the nitrogen atoms of the ring, with a compound of general formula (V)
L1xe2x80x94(CH2)nxe2x80x94Oxe2x80x94Arxe2x80x94Gxe2x80x83xe2x80x83(V)
where Ar and n are as defined earlier and L1 may be a halogen atom such as Cl, Br, I or a leaving group such as methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate etc. and G represents CHO, or NO2 group.
The reaction of a compound of general formula (IV) with a compound of general formula (V) to produce a compound of general formula (III) may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, He. The reaction may be effected in the presence of a base such as alkalis like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium, alkali metal amides like sodamide or mixtures thereof. The amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (IV), preferably the amount of base ranges from 1 to 3 equivalents. 1 to 3 equivalents of alkali metal halides based on the amount of compound of formula (IV) such as lithium bromide may be added as an additive. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 150xc2x0 C., preferably at a temperature in the range of 15xc2x0 C. to 100xc2x0 C. The duration of the reaction may range from 0.25 to 24 hours, preferably from 0.25 to 6 hours.
In another embodiment of the invention, the novel intermediate of the general formula (III) defined and obtained above where G is CHO or NO2 group, can be prepared by reacting the compound of the general formula (VI), 
wherein, X, Y, Z, R1, R2, R3 and n are as defined earlier, with a compound of general formula (VII)
L2xe2x80x94Arxe2x80x94Gxe2x80x83xe2x80x83(VII)
where L2 is a halogen atom, G is a CHO or a NO2 group and Ar is as defined earlier.
The reaction of compound of formula (VI) with the compound of formula (VII) to produce a compound of formula (III) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like. The inert atmosphere may be maintained by using inert gases such as N2, Ar or He. The reaction may be effected in the presence of a base such as K2CO3, Na2CO3, NaH. The reaction temperature may range from 20xc2x0 C. to 150xc2x0 C., preferably at a temperature m the range of 30xc2x0 C. to 100xc2x0 C. The duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.
In another embodiment of the present invention, the novel intermediate of general formula (III), where G is a CHO or NO2 group, can also be prepared by the reaction of compound of general formula (VIII) 
where X, Y, Z, R1, R2, R3, n and L1 are as defined earlier with a compound of general formula (IX)
HOxe2x80x94Arxe2x80x94Gxe2x80x83xe2x80x83(IX)
where G is a CHO or NO2 group and Ar is as defined earlier.
The reaction of compound of formula (VIII) with compound of formula (DC) to produce a compound of the formula (III) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar, or He. The reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof. The reaction temperature may range from 20xc2x0 C. -120xc2x0 C., preferably at a temperature in the range of 30xc2x0 C. -100xc2x0 C. The duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
The present invention provides a process for the preparation of novel azolidinedione derivatives of general formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates wherein R1, R2, R3, X, Y, Z, n and Ar are as defined earlier and A represents CR5 where R5 together with R4 represent a bond and B represents a sulfur or a oxygen atom, and futher to a compound of formula (I) wherein R4 and R5 represent hydrogen and all symbols are as defined above, which comprises:
reacting the novel intermediate of the general formula (III) obtained above where G represents CHO group with 2,4-thiazolidinedione or 2,4oxazolidinedione and removing the water formed during the reaction by conventional methods to yield a compound of general formula (X) 
where R1, R2, R3, X, Y, Z, n and Ar are as defined earlier and B represents sulfur or oxygen.
The reaction between the compound of the general formula (III) where G is a CHO group with 2,4-thiazolidinedione or 2,4-oxazolidinedione, to yield compound of general formula (X) wherein B represents a sulfur or an oxygen atom respectively, may be carried out neat in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or mixtures thereof. The reaction temperature may range from 80xc2x0 C. to 140xc2x0 C. depending upon the solvents employed and in the range from 80xc2x0 C. to 180xc2x0 C. when the reaction is carried out neat in the presence of sodium acetate. Suitable catalyst such as piperidinium acetate or benzoate, sodium acetate or mixtures of catalysts may also be employed. Sodium acetate can be used in the presence of solvent, but it is preferred that sodium acetate is used neat. The water produced in the reaction may be removed, for example, by using Dean Stark water separator or by using water absorbing agents like molecular seives. Oxazolidine-2-oxo-4-thione may be used instead of 2,4-oxazolidinedione. However, the thio group needs to be converted to oxo group by oxidation using agents such as hydrogen peroxide or peroxyacids like mCPBA.
The compound of the general formula (X) obtained in the manner described above is reduced by known method to obtain the compound of general formula (XI) 
wherein R1, R2, R3, X, Y, Z, n and Ar are as defined earlier and B represents a sulfur atom or an oxygen atom. The compound of general formula (XI) represents the compound of general formula (I), wherein R4 is hydrogen, A is CR5 where R5 is hydrogen and other symbols are as defined earlier.
The reduction of compound of the formula (X) to yield a compound of the general formula (XI) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be 5-10% Pd/C and the amount of catalyst used may range from 50-300% w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol.
The compound of the general formula (XI) obtained above is converted into its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates by conventional methods.
In another embodiment of the present invention, the compound of the general formula (I) can also be prepared by reacting a compound of the general formula (VIII) defined above with a compound of general formula (XII) 
where R4, A, B and Ar are as defined earlier and R6 is hydrogen or a nitrogen protecting group which is removed after the reaction.
The reaction of compound of formula (VIII) with compound of formula (XII) to produce a compound of the formula (I) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He. The reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NH or mixtures thereof The reaction temperature may range from 20xc2x0 C. -120xc2x0 C., preferably at a temperature in the range of 30xc2x0 C. -80xc2x0 C. The duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
In still another embodiment of the invention, the compound of the general formula (I), where xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 linker is attached to nitrogen atom can be prepared by reacting the compound of the general formula (IV) defined above with a compound of general formula (XIII) 
where L1, n, Ar, A, B, R4 and R6 are as defined earlier and removal of the protecting group when R6 is a nitrogen protecting group.
The reaction of compound of general formula (IV) with a compound of general formula (XIII) to produce a compound of general formula (I) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He. The reaction may be effected in the presence of a base such as alkalis like sodium hydroxide, or potassium hydroxide; alkali metal carbonates like sodium carbonate, or potassium carbonate; alkali metal hydrides such as sodium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide, or mixtures thereof. Multiple solvents and bases can be used. The amount of base may range from 1 to 5 equivalents, preferably 1 to 3 equivalents. 1 to 3 equivalents of alkali metal halides such as lithium bromide may be added as an additive. The reaction temperature may be in the range of 0xc2x0 C. to 120xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 100xc2x0 C. The duration of the reaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hours.
In yet another embodiment of the present invention, the compound of general formula (I), where R1, R2, R3, X, Y, Z, n and Ar are as defined earlier, R4 represents hydrogen and A is CH and B represents S or O can be prepared by the reaction of compound of general formula (XIV) 
where R1, R2, R3, X, Y, Z, n and Ar are as defined earlier, J is a halogen atom like chlorine, bromine or iodine or a hydroxy group and R is a lower alkyl group, with urea when J is a OH group and with thiourea when J is a halogen atom followed by treatment with an acid.
The reaction of compound of general formula (XIV) with urea or thiourea is normally carried out in the presence of alcoholic solvent such as methanol, ethanol, propanol, isobutanol, 2-methoxybutanol, etc or DMSO or sulfolane. The reaction may be conducted at a temperature in the range between 20xc2x0 C. and the reflux temperature of the solvent used. Bases such as NaOAc, KOAc, NaOMe, NaOEt etc. can be used. The reaction is normally followed by treatment with a mineral acid such as hydrochloric acid at 20xc2x0 C. to 100xc2x0 C.
The compound of general formula (XIV) where J is hydroxy group is prepared by the hydrolysis of compound of general formula (XIV) where J is a halogen atom using aqueous alkali at a temperature ranging from 20xc2x0 C. to 100xc2x0 C. followed by reesterification of the hydrolysed acid group by conventional methods.
The compound of general formula (XIV) where J is a OH group may also be prepared from compound of formula (XIV) where J is a halogen atom by reacting with formamide in the presence of water. The amount of formamide used in the reaction ranges from 0.5 to 1.5 mL and water used ranges from 20 xcexcL to 0.1 mL for one mmol of the halo compound (XIV). The reaction is conducted at a temperature ranging from 80xc2x0 C. to 180xc2x0 C., preferably from 120xc2x0 C. to 150xc2x0 C. over a period ranging from 1 to 8 hours.
The compound of general formula (XIV) where J is a halogen atom can be prepared by the diazotization of the amino compound of the general formula (XV) 
where all symbols are as defined earlier, using alkali metal nitrites followed by treatment with acrylic acid esters in the presence of hydrohalo acids and catalytic amount of copper oxide or copper halide.
The compound of general formula (XV) can in turn be prepared by the conventional reduction of the novel intermediate (III) where G is NO2 group and other symbols are as defined earlier.
In another embodiment of the present invention, the compound of general formula (I), where R1, R2, R3, X, Y, Z, n and Ar are as defined earlier and A is nitrogen atom and B is oxygen atom can be prepared by a process which comprises: reaction of novel intermediate of formula (III) where all symbols are as defined above, and G represents a CHO group with NH2OH. HCl to yield a compound of general formula (III) where G represents CHxe2x95x90NOH group and all symbols are as defined earlier, followed by metal borohydride reduction to yield a compound of general formula (XVI) 
where all symbols are as defined earlier.
The reaction of compound of general formula (III), where G is CHO group and other symbols are as defined earlier, with hydroxylamine hydrochloride is carried out in solvents such as ethanol, methanol, THF, dioxane and the like following the conventional method to make oximes. 1 to 10 equivalents of NH2OH.HCl may be used, preferably, 2 to 5 equivalents. Bases such as alkali metal acetates or ammonium acetate may be used. Reaction may be carried out in the presence of water. Temperature in the range of 0xc2x0 C. to reflux temperature of the solvent may be used. The oxime obtained in the manner described above is reduced using reducing agents such as alkali metal borohydrides like sodium borohydride or sodium cyanoborohydride or borane reagents using conventional conditions to yield the compound of general formula (XVI).
The compound of general formula (XVI) in turn is reacted with halocarbonyl isocyanate or alkoxycarbonyl isocyanate to yield a compound of general formula (I) or with KOCN to yield a compound of general formula (III) where G is CH2N(OH)CONH2, followed by treatment with carbonylating agents such as alkyl haloformate to produce the compound of general formula (I) where R1, R2, R3, X, Y, Z, n, Ar are as defined earlier, A represents nitrogen atom and B is oxygen atom.
The reaction of compound of general formula (XVI) with halocarbonyl isocyanate such as chlorocarbonyl isocyanate or alkoxycarbonyl isocyanate such as ethoxycarbonyl isocyanate may be carried out in inert solvents such as THF, dioxane, etc at a temperature in the range xe2x88x9215xc2x0 C. to 50xc2x0 C. The reaction may be carried out for 0.5 to 12 hours depending on the substrates used for the reaction.
Alternatively, the compound of general formula (XVI) may be treated with excess of KOCN in organic acids such as acetic acid. Water may be used in the reaction. The reaction may be carried out at a temperature in the range of 20xc2x0 C. to 120xc2x0 C. The product isolated in the reaction is further treated with alkyl haloformate such as ethyl chloroformate in the presence of 1 to 10 equivalents of alkali such as sodium hydroxide, potassium hydroxide and the like to obtain compound of general formula (I) where all the symbols are as defined earlier and A represents nitogen atom and B represents oxygen atom.
In yet another embodiment of the invention, the compound of general formula (I), where the linker xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 is attached through Z, where Z represents xe2x95x90C, and all other symbols are as defined earlier can be prepared by reacting the compound of general formula (XVII) 
where R1, R2, and R3 are as defined earlier, X represents Cxe2x95x90O or Cxe2x95x90S and Y represents Cxe2x95x90C; or when R2 and R3 together with Y form a cyclic structure as defined earlier, X represents Cxe2x95x90O or Cxe2x95x90S, Y represents Cxe2x95x90C and R1 is as defined earlier, with a compound of general formula (XVIII) 
where Ar, R4, A, B and n are as defined earlier, D may be xe2x80x94CN; xe2x80x94C(OR7)3 where R7 is (C1-C4)alkyl; xe2x80x94C(xe2x95x90O)xe2x80x94R8 where R8 may be selected from xe2x80x94OH, Cl, Br, I, xe2x80x94NH2, xe2x80x94NHR, OR where R is a lower alkyl group such as methyl, ethyl, propyl and the like, or R8 may be Oxe2x80x94(Cxe2x95x90O)xe2x80x94R9, where R9 may be a linear or branched (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl groups. The reaction proceeds through the intermediate formation of compound of general formula (XIX). 
where all symbols R1, R2, R3, R4, X, Y, A, B, Ar and n are as defined earlier.
The group Xxe2x80x94NHR1 in formula (XIX) can also be generated by conventional methods such as amidation of an ester group (XOR) or partial hydrolysis of a CN (in a compound where CN group is present in the place of Xxe2x80x94NHR1) group.
The reaction of compound of general formula (XVII) with a compound of general formula (XVIII) to produce a compound of general formula (I) may be carried out in neat or in the presence of solvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be carried out at a temperature in the range of 50xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 60xc2x0 C. to 180xc2x0 C. The reaction may be effected in the presence or in absence of a base or an acid. The nature of the base or the acid is not critical. Example of such bases include organic bases such as pyridine, lutidine, triethyl amine, diisopropylethyl amine and the like, metal carbonates such as K2CO3, Na2CO3. Examples of acids include organic acids such as AcOH, C2H5COOH, butyric acid, p-toluenesulfonic acid, benzenesulfonic acid and the like, mineral acids such as HCl, HBr etc. The duration of the reaction may range from 0.25 to 48 hours, preferably from 0.50 to 18 hours.
Alternatively, the novel intermediate of formula (XIX) may be isolated and then cyclised to yield a compound of formula (I).
The reaction of compound of the formula (XVII) with a compound of formula (XVIII) to yield a compound of the formula (XIX) may be carried out neat or in presence of solvent such as xylene, toluene, dioxane, DMF, DMSO, halogenated hydrocarbons such as CH2Cl2, CHCl3, ClCH2CH2Cl and the like or mixtures thereof. The reaction may be effected in the presence or absence of a base or an acid. The nature of the base or acid is not critical. Examples of such bases include organic bases such as pyridine, lutidine, triethyl amine, diisopropylethyl amine and the like. Examples of acids used for this reaction includes CH3COOH, C2H5COOH, butyric acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be carried out at a temperature in the range of 25xc2x0 C. to 180xc2x0 C., preferably in the range of 25xc2x0 C. to 100xc2x0 C. The reaction is generally instantaneous and the duration of the reaction may range from 0.25 to 24 h, preferably 0.25 to 2 h.
The cyclisation of the compound of formula (XIX) to yield a compound of the formula (I) may be carried out neat or in the presence of solvents such as THF, toluene, xylene, 1,4-dioxane and the like or mixtures thereof. The reaction temperature may range from 60xc2x0 C. to 150xc2x0 C. depending upon the solvent employed and in the range from 100xc2x0 C. to 200xc2x0 C. when the reaction is carried out neat. The reaction may be effected in presence or absence of acids. The acids normally used include acetic acid, propionic acid, butyric acid, pTsOH and the like. The amount of acid used may range from 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents. The reaction can also be carried out in neat acid. The reaction is preferably carried out in solvents such as THF, toluene, xylene, 1,4-dioxane or mixtures thereof in the presence of an acid such as acetic acid, propionic acid, p-TsOH and the like. The duration of the reaction may range from 3 to 48 h preferably from 4 to 18 h.
The process described in the above embodiment is novel and unique since the heterocycle has been built in the final step of the process. In the present process no side products are observed. The yields are high and no purification is required for any intermediate involved. The process described in the above embodiment does not involve any stringent conditions. This process works well for both small scale and large scale reactions. The process described in the above embodiment is preferably used for compounds of formula (I) wherein R2 and R3 together form a cyclic structure as defined earlier with Y, wherein Y represents Cxe2x95x90C.
The compound of general formula (XVIII) where D represents xe2x80x94COOH and all other symbols are as defined earlier is prepared from the compound of general formula (XVIII) where D represents xe2x80x94COOR where R is a lower alkyl group such as CH3, C2H5, C3H7 and all other symbols are as defined earlier by conventional hydrolysis procedures.
The hydrolysis of the compound of formula (XVIII) where D represents COOR group to yield a compound of the formula (XVIII) where D represents COOH group, may be carried out in the presence of solvents such as methanol ethanol, dioxane, ether, THF, water and the like or mixtures thereof. The reaction may be effected in the presence of a base such as an alkali like NaOH, KOH or alkali metal carbonates like sodium carbonate, potassium carbonate and the like. The amount of base may range from 1 to 5 equivalents. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 120xc2x0 C., preferably at a temperature in the range of 15xc2x0 C. to 100xc2x0 C. The duration of the reaction may range from 0.25 to 24 h, preferably from 0.5 to 5 h.
The compound of general formula (XVIII) where D represents COCl or COBr and other symbols are as defined earlier may be prepared by the reaction of compound of general formula (XVIII) where D represents COOH and other symbols are as defined earlier with reagents such as SOCl2, PCl3, PCl5, PBr3 and the like. The reaction may be carried out neat or in the presence of solvents such as benzene, xylene etc. The reaction may be carried out in the range of 0xc2x0 C. to 140xc2x0 C. preferably in the range of 25xc2x0 C. to 100xc2x0 C. The duration of the reaction may range from 0.25 to 24 h, preferably 0.5 to 5 h.
The compound of general formula (XVIII) where all symbols are as defined earlier and D represents xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94R9, where R9 represents a linear or branched (C1-C5) alkyl group, dichlorophenyl, trichlorophenyl group and the like, may be prepared by the reaction of compound of general formula (XVIII) where D represents COOH and all other symbols are as defined earlier, with organic acid halides such as acetyl chloride, acetyl bromide, propanoyl chloride, butanoyl chloride, pivaloyl chloride, trichlorobenzoylchloride and the like in the presence of a base such as pyridine, N,N-dimethylaminopyridine, triethyl amine, diisopropylethyl amine, lutidine and the like or a mixture thereof. The reaction may be carried out in solvents such as CH2Cl2, CHCl3, ClCH2CH2Cl, 1,4-dioxane, xylene and the like. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 120xc2x0 C., preferably in the range of 0xc2x0 C. to 50xc2x0 C. The duration of the reaction may range from 0.25 to 12 h, preferably 0.5 to 5 h.
Particularly useful compound of general formula (I) where X represents Cxe2x95x90O, Y represents Cxe2x95x90C, Z represents xe2x95x90C, n represents an integer 1, R1 represents methyl group, B represents sulfur atom, R2 and R3 together with Y form a phenyl ring represented by formula (XX) can be prepared according to the process described in the above embodiment comprising: 
a) Reducing a compound of formula (XXI) which is disclosed in JP 2558473
where R10 is a lower alkyl group such as methyl, ethyl and the like using conventional reduction conditions to yield a compound of formula (XXII) 
where R10 is as defined above.
The reduction of compound of the formula (XXI) to yield a compound of the formula (XXII) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C or Raney nickel. Mixtures of catalysts may be used. Solvents such as dioxane, acetic acid, ethyl acetate and the like may be used. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be 5-10% Pd/C and the amount of catalyst used may range from 50-300% w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol.
b) Hydrolysis of compound of formula (XXII) using conventional conditions to yield a compound of formula (XXIII) 
The hydrolysis of the compound of formula (XXII) to yield a compound of the formula (XXIII) may be carried out in the presence of solvents such as methanol ethanol, dioxane, ether, THF, water and the like or mixtures thereof. The reaction may be effected in the presence of a base such as alkali like NaOH, KOH, alkali metal carbonates like sodium carbonate and potassium carbonate. The amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (XXII). The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 120xc2x0 C. preferably at a temperature in the range of 15xc2x0 C. to 100xc2x0 C. The duration of the reaction may range from 0.25 to 24 h, preferably from 0.5 to 5 h.
c) Reacting a compound of formula (XXIII) with acid halide or halogenating agent to obtain a compound of formula (XXIV), 
where D represents COCl or COBr or xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94R9, where R9 represents methyl or t-butyl group.
The reaction of compound of formula (XXIII) with halogenating agent such as SOCl2, PCl5, PBr3 may be carried out neat or in presence of solvent such as benzene, xyene etc. The reaction may be carried out at 0xc2x0 C. to 140xc2x0 C., preferably at 25xc2x0 C. to 100xc2x0 C. The duration of the reaction may range from 0.25 to 24 h, preferably 0.5 to 5 h. The reaction of compound of formula (XXIII) with acid halide to yield mixed anhydride, may be carried out with acid halides such as acetyl chloride or pivaloyl chloride in the presence of a base such as pyridine, triethyl amine, N,N-dimethylamino pyridine or mixtures thereof. The amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (XXIII). The reaction may be carried out in solvents like dichloromethane, chloroform, dichloroethane, 1,4-dioxane, xylene and the like. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 120xc2x0 C., preferably at a temperature in the range of 15xc2x0 C. to 50xc2x0 C. The duration of the reaction may range from 0.25 to 12 h preferably from 0.5 to 5 h.
d) Reaction of compound of formula (XXIV) with a compound of formula (XXV) 
to yield a compound of formula (XX) defined above. The reaction proceeds through the intermediate formation of compound of formula (XXVI). 
The reaction of compound of formula (XXIV) with a compound of formula (XXV) to produce a compound of general formula (XX) may be carried out in neat or in the presence of solvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be carried out at a temperature in the range of 50xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 80xc2x0 C. to 180xc2x0 C. The reaction may be effected in the presence of an acid. The nature of the acid is not critical. Examples of acids include organic acids such as AcOH, C2H5COOH, p-toluenesulfonic acid and the like, mineral acids such as HCl, HBr etc. The duration of the reaction may range from 0.25 to 48 hours, preferably from 0.50 to 18 hours, based on solvent, temperature and acid used.
Alternatively, the novel intermediate of formula (XXVI)) may be isolated and then cyclised to yield a compound of formula (XX).
The reaction of compound of the formula (XXIV) with a compound of formula (XXV) to yield a compound of the formula (XXVI) may be carried out neat or in presence of solvent such as xylene, toluene, dioxane, DMF, DMSO halogenated hydrocarbons such as CH2Cl2, CHCl3, ClCH2CH2Cl and the like or mixtures thereof. The reaction may be effected in the presence of an acid. The nature of the acid is not critical. Examples of acids used for this reaction includes CH3COOH, C2H5COOH, butyric acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be carried out at a temperature in the range of 25xc2x0 C. to 180xc2x0 C., preferably in the range of 25xc2x0 C. to 60xc2x0 C. The reaction is generally instantaneous and the duration of the reaction may range from 0.25 to 12 h, preferably 0.25 to 2 h.
The cyclisation of the compound of formula (XXVI) to yield a compound of the formula (XX) may be carried out neat or in the presence of solvents such as THF, toluene, xylene, 1,4-dioxane and the like or mixtures thereof. The reaction temperature may range from 60xc2x0 C. to 150xc2x0 C. depending upon the solvent employed and in the range from 100xc2x0 C. to 200xc2x0 C. when the reaction is carried out neat. The reaction may be effected in the presence of acids. The acids normally used include acetic acid, propionic acid, and pTsOH. The amount of acid used may range from 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents. The reaction can also be carried out in neat acid. The reaction is preferably carried out in solvents such as THF, toluene, xylene, 1,4-dioxane or mixtures thereof in the presence of an acid such as acetic acid, propionic acid, p-TsOH and the like. The duration of the reaction may range from 3 to 48 h preferably from 4 to 18 h, based on solvent, temperature and acid used.
The term neat as used herein means the reaction is carried out without the use of solvent.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaplithoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like or chiral bases such as rucine, cinchona alkaloids and their derivatives and the like.
Various polymorphs of compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffractogram or such other techniques.
The present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I), as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment and/or prophylaxis of diseases in which insulin resistance is the underlying pathophysiological mechanism such as type II diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis; insulin resistance associated with obesity and psoriasis, for treating diabetic complications and other diseases such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 20%, preferably 1 to 10% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
A typical tablet production method is exemplified below:
Tablet Production Example
The ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure. The ingredient 4 and 5 are mixed well with the granules and compressed by tabletting machine to prepare 1000 tablets each containing 10 mg of active ingredient.
The ingredients 1 to 4 are uniformly moistened with an aqueous solution of ingredient 5 and granulated after drying under reduced pressure. Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 10 mg of active ingredient 1.
The compound of the formula (I) as defined above are clinically administered to mammals. including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.10 to about 200 mg/kg body weight of the subject per day or preferably about 0.10 to about 30 mg/kg body weight per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.